At a time when the small-molecule pipeline of the pharmaceutical industry is beginning to run dry, the number of macrocycles has increased in an explosive manner. This fast-growing phenomenon is due to the discovery of an impressive number of new families of natural, semi-synthetic, and synthetic compounds, which possess extraordinary properties. The macrocyclic structure is a particularly desirable feature for the pharmaceutical industry. The cyclic structure stabilizes the molecule against destruction by the human body and increases its effectiveness in comparison with its linear analog, by constraining it to a biologically active form. Accordingly, macrocycles constitute a major class of pharmaceutical agents that are currently under wide-spread clinical investigation.
Moreover, macrocycles are key components in many other fields, including nanotechnology. Nanoscale devices such as chemical noses for the detection of land mines, sensors for the detection of chemical weapons, light rods for solar energy conversion, photovoltaic cells, light emitting diodes, magnetic materials, multi-bit storage devices, and semi-conducting materials have already been fashioned using macrocyclic compounds.
In spite of their great potential, however, macrocycles have remained relatively under-explored and unexploited. Current methods used for the preparation of macrocycles severely limit their use in medicine and other important industries. While some of these compounds are available from biological sources in quantities sufficient for basic research or initial clinical studies, others need to be produced by semi- or total synthesis. The present methodologies for producing macrocycles require hundreds of man-hours of work, produce large amounts of toxic waste, require expensive manufacturing facilities, and still produce frustratingly low quantities of the desired material. Low production yield renders the profit margins of these molecules too small for commercial production. Consequently, due to the high costs and low profit margins associated with production of macrocycles by conventional chemical manufacturing approaches, many important discoveries are not commercialized. More importantly, the staggering potential of macrocyclic research and development is largely unrealized, as the result of the inability of the art to provide a practical method for making such compounds.
Thus, the inability to obtain large quantities of macrocyclic molecules has been, and still is, the major stumbling block for their commercial exploitation, as well as the stimulus for efforts to improve existing methods or to discover new ones.
Conceptually, the synthesis of cyclic molecules begins with the preparation of open-chained starting materials which are cyclized by a ring closure reaction. In contrast to the efficient formation of five- or six-member rings, however, problems are encountered when cyclization of compounds of other sizes, both smaller and larger, is carried out in practice: yields of small rings (3-4 atoms) are low and even lower for medium rings (8-12 carbon atoms) and macrocycles (>12 atoms). Due to ring strain effects, small rings are less stable than five- or six-member rings, and thus they are more difficult to obtain. However, most macrocycles are unstrained and their enthalpy of formation is comparable to that of five- or six-member rings. Thus, there are no thermodynamic barriers to the formation of unstrained macrocycle. Nonetheless, the kinetics of the formation of macrocycles greatly complicates their formation. For entropic reasons, it is more difficult to synthesize macrocycles than small and medium ring compounds because macrocyclic ring formation involves a low probability for coincident positioning of the two ends of the open chain starting material, as required for cyclization to occur. Further, intermolecular reactions of the reactive ends of the linear precursor compete with the cyclization reaction. Such intermolecular reactions lead to formation of undesired oligomers and polymers.
In order to circumvent these undesirable oligomerization reactions, cyclization is generally carried out under relatively dilute conditions (typically less than 10 mM). The rationale for the high dilution synthesis method is that if the concentration of the reactants is sufficiently low, then the ring closure reaction will be favored, since the reactive ends thereby are isolated from the reactants and therefore more likely to react in an intramolecular fashion to effect ring formation. However, the high dilution principle is most effective if the cyclization reaction is an irreversible reaction and the rate of cyclization is greater than the rate of polymerization. In contrast to this kinetic approach, in a thermodynamically controlled, reversible reaction, the relative stabilities of all products, macrocyclic or acyclic, determine the product distribution. If the macrocycle is the most stable compound in such reversible reaction system, then the macrocycle will be formed in good yield. Indeed, some examples exist where macrocycles are in fact formed as the most stable products in a reversible reaction. However, in most cyclization reactions, macrocycles and undesired oligomers and polymers are of comparable thermodynamic stabilities and therefore, all of them will exist as a complex mixture, which requires extensive and complicated purification procedures in order to obtain the desired macrocyclic material. Furthermore, high dilution methods can only provide limited quantities of the macrocyclic material and are therefore inappropriate for high-volume commercial production.
In order to overcome or mediate the above-described difficulties and complications, a wide variety of modifications and improvements have been made to the high dilution methods, by adapting such methods to the individual requirements of specific target molecules. These approaches have achieved a wide variety of levels of success, on a molecule by molecule basis. For example, it is now possible to prepare modest quantities of certain macrocycles by appropriate choice of starting material, solvent, temperature, catalyst and dilution conditions, often with the assistance of other effects, e.g., the template effect, the rigid group principle, and other pseudo-dilution phenomenon.
In supramolecular chemistry, for example, the use of an appropriate template can greatly improve cyclization steps. For those examples where the building blocks for the macrocycle and its oligomers are the same, an organic or inorganic guest material (i.e., a template) may be found which binds complementarily into the cavity formed by the macrocycle. Under reversible conditions, the resulting supramolecular complex will be more stable than the macrocyclic component and thus favored, which is known as the template effect. In addition to mixtures in equilibrium, the template effect can also be useful in kinetically controlled reactions when the template facilitates the intramolecular reaction by pre-organizing the reactive ends. Important features in high yield template-assisted cyclization reactions include the geometry of the template material, and the number of heteroatoms in the interior cavity of the macrocycle that are available for coordinating with the template.
In addition to template materials that bind to a cavity formed by the macrocycle, other materials with microporous structures can pre-organize the reactive ends of the reactants and thereby facilitate the ring closure reaction, by providing a localized environment defined by the microporous structure that is highly favorable to the ring closure reaction. For example, Smectite clays have been used to provide substantial improvements in yield and/or selectivity of macrocyclic compounds. The predetermined architectures of the microporous structures in the clays can be effectively used to pre-organize the reactive substances in a manner that controls the extent of oligomerization and the geometry of the macrocycle so formed. Subsequently, the final macrocyclic product can be removed from the clay framework.
Further, some structural elements have emerged that show a propensity to bend linear structures and form pre-organized ring structures, suggesting that such pre-organization can be used to favor intramolecular processes over the intermolecular ones and provide simple routes for the preparation of macrocyclic structures. This predisposition of certain molecules to bending or folding has been widely studied, e.g., the Thorpe-Ingold effect, and several structural elements, such as urea and proline residues, have been identified as being associated with the formation of U-turns in natural products. Consequently, sterically encumbering groups can be added to acyclic precursors to effectuate bending thereof and to facilitate ring closure, when the target macrocyclic compound does not normally contain such sterically encumbering groups.
Recent years have witnessed a renaissance in the field of peptides. At present, more than 40 peptides are on the market, many more are in registration processing, hundreds are in clinical trials and more than 400 are in advanced preclinical studies. The enhanced biological specificity, activity, and metabolic stability of cyclopeptides in comparison with those of the linear peptides, as a result of the constrained structural features of the cyclic peptides, have attracted much attention. Cyclic peptidomimetic scaffolds and templates have been widely used to assemble a wide variety of spatially defined functional groups for molecular recognition and drug discovery. There is a vigorous, on-going effort to device and develop commercially applicable synthetic methods for preparation of cyclic peptides and peptidomimetics.
Cyclic peptides can be synthesized from partially protected linear precursors formed in solution or by solid-phase techniques involving cyclization of such linear precursors in solution under high or pseudo-dilution conditions. Alternatively, cyclic peptides can be prepared by solid-phase assembly of the linear peptide sequence, followed by cyclization while the peptide remains anchored to a polymeric support. This method takes advantage of the pseudo-dilution phenomenon attributed to the solid-phase, which favors intramolecular reactions over intermolecular side reactions. More recently, chemical ligation methods have also shown some success in the formation of cyclic peptides, specifically in the formation of backbone peptide bonds. Unlike other methods, chemical ligation methods do not require coupling reagents or protection schemes, but are achieved through a variable chemoselective capture step followed by an invariable intramolecular acyl transfer reaction.
Despite the development of the above-discussed synthesis techniques and other high-dilution or pseudo-dilution methods, however, the practical aspects of the synthesis principle, viz., the selection of starting materials and reaction parameters, still have to be determined empirically, and the cyclization step still remains as the fundamental synthetic challenge. The requirements for complex multi-step processes, specific reaction conditions, templates, selective protection/deprotection steps, and high dilution of the reaction materials continue to restrict commercial production of macrocyclic compounds, even after extensive optimization, and the modified or improved methods still suffer from many limitations of the original high-dilution procedure.
A general method that does not depend on high dilution of the reaction materials or otherwise suffer the deficiencies of high dilution techniques and is useful for synthesis of a wide variety of macrocyclic compounds on a commercial scale would be of immense value.